1. T cells. Phenotype, function, fallacies. Jan Novák

2. T cells Central role in the immune system Recognition of antigens Direct effect on the antigens Coordination of the immune response Suppression of the immune responses

3. T cells versus B cells Minimal morphological differences Differentiation based on the detection of surface markers B cells: CD19, B220, T cells: TCR, CD3, CD4, CD5, CD8 etc.

4. Phenotype of T cells T cell receptor (TCR) Other receptors involved in the antigen recognition and signalization (CD4, CD8, CD3) Receptors and molecules involved in the migration of T cells Receptors for cytokines Activation markers (CD25, CD28, CD69)

5. Groups of T cells  T cells T-helpers (CD4+) Th1 Th2 Th3 Cytotoxic T cells (CD8+) NKT cells Regulatory T cells (CD4+CD25+)  T cells

6. CD4+ T lymfocyty – T helpers IL-12 IL-4 TGF-  Th1 Th2 Th3 Th0 APC Th0 TGF-  IL-6 Th17

7. Th1 cells Inflammatory cells Help to macrophages Activation, stimulation of their killing activities  Elimination of intracellular agents Help to T cells Proliferation, Th1 differentiation Production of cytokines (IFN-  TNF-  IL-2)

8. Th1 cells Clearance of intracellular pathogens Delayed type of hypersensitivity Autoimmune diseases

9. Th2 cells Help to B cells Development Antibody production Regulatory functions Production of cytokines (IL-4,IL-5,IL-6,IL-13)

10. Th2 cells Defense against extracellular agents Participation in allergic reactions Th3

11. Th3 cells Develop in the presence of TGF- , IL-10 and IL-4 Secretion of TGF-  and IL-10 Induced after oral administration of antigens, play a role in the induction of oral tolerance Th3

12. Th17 Development in the presence of TGF-b a IL-6, IL-21, IL-23 Secretion of IL-17, IL-21, IL-22 Proinflammatory cytokines Role in the immune defense against Klebsiella a citrobacter Contribution ion the pathogenesis of some organ-specific autoimmune diseases in experimental model Th3

13. Cytotoxic CD8+ T cells Elimination of dangerous cells of the body Elimination of cells infected by intracellular pathogens Elimination of stressed cells (tumors, damaged cells)

14. Killing by CD8+ T cells Perforin-granzyme system (degranulation, perforation, apoptotic death) Fas-FasL interaction (apoptotic death) Cytokine dependent -lymphotoxin (apoptotic death)

15. CD8+ T cells in immune reactions Clearance of infection Onco-immunosurveillance

16. Regulatory T cells CD8+ T cells are not supressors!!! CD4+CD25+ T cells Th3 T cells T reg cells NKT cells  T cells

17. Functions of regulatory T cells Inhibition of the immune responses Maintenance of immunological tolerance Regulation of exagerated reaction against infection Supresssion of anti-tumor responses

18. Functions of regulatory T cells Cell-contact dependent mechanisms Secretion of cytokines (IL-4, IL-10, TGF-  ) Killing of effector cells

19. NK cells NK = natural killer Large granular lymphocytes Development in bone marrow

20. Immune reactions of NK cells Functions antigen-non specific Recognition of unknown structures on the surface of target cells

21. Immune reactions of NK cells The function of NK cells is a result of the interaction of their inhibitory and activation receptors Activation: Fc receptor CD16 ADCC – antibody-dependent cellular cytotoxicity Inhibition – killer inhibitory receptors (Ly49, CD94-NKG2)

22. Immune reactions of NK cells Cytotoxicity – perforin-granzyme dependent

23. Immune reactions of NKT cells Natural Killer T cells Phynotypic and functional features of both NK and T cells

24. Immune reactions of NKT cells Natural Killer T cells Phynotypic and functional features of both NK and T cells Restriction by MHC class I like molecule CD1d presenting glycolipids and lipids

25. Phenotype of NKT cells Expression of TCR, CD3, CD4 Expression of markers of NK lineage Biased TCR repertoire Recognition of conserved glycolipid structure presented by CD1d

26. Functions of NKT cells Secretion of both, Th1 and Th2 cytokines Impact on Th1/Th2 differentiation of naive T cells Activation of B cells Activation of NK cells Activation of dendritic and other ather antigen presenting cells Cytotoxic functions Regulatory functions

27. T cells in the development of diseases Defence against infection - immunodeficiencies Allergic reactions Autoimmunity Oncological diseases

28. Immunodeficiencies Primary (SCID, RAG, common  chain) Secondary (HIV, tumors, metabolic disorders, malnutrition, sepsis)

29. Immunodeficiencies clinical features Life-threatening – asymptomatic relapsing infections (viruses, fungi, intracellular bacterias)

30. Human immunodeficiency virus Retrovirus, RNA virus Targets selectively CD4+ T cells, macrophages and dendritic cells

31. HIV infection 1. 3-12 weeks after infection: Flu-like syndrom 2. Asymptomatic period, decrease of CD4+ T cells, production of anti-HIV antibodies

32. HIV infection 3. AIDS related complex: generalized lymphadenopaty, diarrhoe, candidiasis, fever

33. HIV infection 4. AIDS: infekce oportunními patogeny pneumocysty, kryptokoky, toxoplazmoza, CMV retinitis, enteritidis, pneumonitis, encefalitis, maligní nádory - Kaposhi sarkom, primární lymfom mozku, NHL B, HIV encefalopatie

34. Allergic and hypersensitive reactions Type 1 of immunopotahologic reactions Pathological production of IgE antibodies 1.: binding of IgE on mast cells and bazofiles, degranulation and histamine, bradykinine release  oedema 2.: eozinofiles, Th2 cells – secretion of leukotriens a prostaglandines  smooth muscle constriction Participation of Th2 and NKT cells, production of IL-4, IL-13.

35. Allergic and hypersensitive reactions Evolutionary – reactions against worms and parazites Allergic reactions – orms, parazites, dust, food antigens…

36. Autoimmunity Reaction of the immune system against body- own tissues Failure of the immune system to eliminate autoreactive T cells (central, peripheral tolerance).

37. Autoimmune diseases Th1 biase of autoreactive T cells Prevention of the disease by Th2 switching Participation of Th1 and CD8+ T cells in tissue destruction by cytotoxic mechanisms and cytokines

38. Autoimmunity Decreased numbers and impaired function of regulatory T cells in experimental animals and patients suffering from autoimmune diseases

39. Oncoimmunology The immune system has the capacity to detect and to destroy tumor cells The animals deficient in T cells develop tumors in increased frequencies Increased incidence of tumor in immunosupprimed patients

40. Why immune system does not destroy all tumor cells? The same HLA phenotype Impaired antigen presentation by tumor cells The selection of less immunogenic cells in the tumor Production of immunosuppressive factors by tumor cells

41. Can we treat oncologic patients by the manipulation of the immune system? Detection of Tu-specific or Tu-associated antigens CEA,  -fetoprotein, MAGE

42. Can we treat oncological patients by the manipulation of the immune system? Immunostimulation Vaccines based on the enhancement of Tu presentation In vitro expansion of Tu Ag specific T lymphocytes

43. Vaccines against oncological disorders Cancer of cervicis uteri Vaccination against papilomaviruses

44. Literature Immunobiology – The immune system in health and disease: Charles A. Janeway Jr., Garland Publishing, 2001 The autoimmune diseases: Noel A. Rose, Academic Press – Third edition, 1998 Medical Immunology: Tristam G. Parslow, Lange – Tenth edition, 2001 Nature Reviews Immunology